tbuckley/cabot-search huggingface dataset:
Training community health workers to increase advanced care planning in African American women with breast cancer.
Authors: Dario Martin Villamar, Clarissa Huard, Lian Ariel Nicholson, Patricia Moreno, Marcia Tan
Journal: Journal of Clinical Oncology (2022)

e18549 Background: Black women are more likely to be diagnosed with more aggressive subtypes of breast cancer, at more advanced stages, and have worse outcomes than white women. Rates of advanced care planning (ACP) discussions are lower among black patients with advanced cancer, and they are less likely to receive care concordant with their wishes at end of life. Community health workers (CHW) play a versatile role in bridging social barriers to care and offer a unique mechanism to improve ACP discussions in this population. The aim of our study was to use a mixed methods approach to examine current practices and strategies to facilitate integration of CHW in ACP with black women with breast cancer. Methods: Participants completed a 22-item questionnaire to assess prior training in ACP and experience serving cancer patients. Focus groups were conducted with CHW (N = 5) and providers (i.e., oncologists, radiation oncologists, and palliative medicine physicians; N = 6) to discuss knowledge of ACP, barriers to ACP discussions, strategies to integrate CHW into ACP, and components of an effective ACP training curriculum for CHW. Focus groups were transcribed and two independent coders analyzed the data using the Framework method to extract themes and components of an ACP training curriculum for CHW. Results: Approximately 60% of CHW reported having received prior training in ACP. All providers reported primarily serving Black patients, and 66% self-reported low rates of ACP documentation (10-25%) among their patients. In the focus groups, CHW and providers described elements of effective ACP discussions as patient value-focused, multidisciplinary, timely, and empowering. Common barriers to ACP discussions identified by CHW included inexperience with ACP, unclear responsibility to initiate the discussion, and patient factors such as reluctance and complex social dynamics; providers identified issues of mistrust, historic injustice and power dynamics with their patients. Both CHW and providers viewed the role of CHW in ACP as a longitudinal process to empower, educate and reinforce patients’ values via a non-judgmental member of the community. For both groups, an ideal training curriculum teaches about key oncologic concepts, assesses patient readiness, and increases familiarity with ACP documentation. Conclusions: CHW serve a vital role in bridging care gaps for vulnerable patients and provide an opportunity to improve rates of ACP discussions in Black women with breast cancer. A training curriculum designed to help CHW assess a patient’s understanding of ACP and reinforce a longitudinal conversation is feasible, straightforward and can be incorporated into CHW workflow. One such training curriculum could expose CHW to different ACP documents, provide simulated patient encounters, and educate CHW on verbal and non-verbal cues from providers that may signal an ACP discussion is needed.
Efficacy and toxicity of antibody-drug conjugates (ADCs) in the treatment of metastatic urothelial cancer (mUC): A systematic review.
Authors: Tiago Costa de Padua, Greta Malena, Marco Moschini, Alberto Martini, Laura Marandino, Daniele Raggi, Alberto Briganti, Francesco Montorsi, Andrea Necchi
Journal: Journal of Clinical Oncology (2022)

e16536 Background: mUC is an aggressive disease with limited overall survival. Recently, immunotherapy with checkpoint inhibitors (ICI) has dramatically improved outcomes but with limited response rates and overall survival. ADC were designed with the intent to deliver potent cytotoxic drugs selectively to antigen-expressing tumor cells by linking cytotoxins to mAbs and have emerged as a new option of treatment with promising results. We aimed to realize a systematic review of efficacy, treatment-related AEs (trAEs) and impact on quality of life of ADC in mUC. Methods: A systematic review of the literature has been performed in January 2022 using Pubmed and Embase database according to the Preferred Reported Items for Systematic Reviews and Meta-analyses (PRISMA) statement. After excluding review, duplicate and non-relevant articles, 10 clinical trials were included in the analysis. The search method involved querying for the terms bladder carcinoma or urothelial carcinoma with any of the following: enfortumab vedotin (EV), sacituzumab govitecan (SG), antibody-drug conjugate. Only prospective clinical trials were included. Results: The systematic review yielded 1103 records using MEDLINE (741 records) and EMBASE (362 records). Ultimately, 9 phase 1, 2 or 3 clinical trials with 1355 patients were selected for inclusion and 4 drugs were identified: Enfortumab vedotin (EV), sacituzumab govitecan (SG), an anti-HER2 compound (RC48-ADC), and an anti- SLITRK6 drug (ASG-15ME). Efficacy outcomes are presented in table 1. Phase 2 trials have reported promising response rates in mUC and one randomized phase 3 trial showed the superiority of EV vedotin over CT after failure to platinum-based CT and ICI with improvement in overall survival. TRAEs of any grade occurred in more than 90% of patients in phase 2 or 3 trials, with high rates of discontinuation (table 2). TRAEs of special interest related to EV were rash, neuropathy, and hyperglycemia. SG is associated with diarrhea and hematologic toxicity. Data from phase 2 and 3 trials of EV suggest no impact on quality of life and an improvement in some parameters. Conclusions: ACDs represent a very promising new option for the treatment of mUC. A phase 3 trial confirmed the superiority of EV over CT after platinum and IO failure. A high incidence of potential adverse events was observed in phase 2 and 3 trials, including rash, neutropenia, hematologic toxicity, and neuropathy. Practitioners’ oncologists should be aware of potential adverse events and optimal management. Quality of life is preserved during the treatment with EV.
Melanoma mortality rate trend in an era of effective treatments: A retrospective study, 1975-2019.
Authors: Navkirat Kahlon, Danae M. Hamouda
Journal: Journal of Clinical Oncology (2022)

e21555 Background: Skin cancer is the most common cancer in the US. Among all skin cancer cases, melanoma represents only about 1%, but it causes most of the deaths due to skin cancer. Unfortunately, the incidence of melanoma has increased over the last three decades. In the past decade, new and effective therapies for melanoma have emerged, with FDA-approval of multiple checkpoint inhibitors (such as PD-1 inhibitors and CTLA4 inhibitors), and multiple tyrosine kinase inhibitors (TKIs) targeting v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutated melanoma. The aim of this study is to review mortality trends in melanoma since the FDA-approval of these agents. Methods: Long term age adjusted cutaneous Melanoma Mortality Rate (MMR) trends in the United States were reviewed and evaluated using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program from 1975 to 2019. The Annual Percent Change (APC) with 95% confidence interval (CI) and p-value has been used to report long term trends. APC has been calculated using Joinpoint regression. Results: The MMR was found to be increased during 1975-1988 (APC 1.65%; p &lt; 0.01). No statistically significant change in MMR was seen during 1988-2013 (APC 0.01%; p = 0.85). MMR was significantly decreased during 2013-2017 (APC -6.24%, p &lt; 0.01). No statistically significant decrease has been seen during 2017-2019 (APC -1.56%, p = 0.53); however, there is a downward trend. Conclusions: This SEER database retrospective review of MMR provides the insight into change in long term mortality trends for melanoma in the United States. During 1975-2019, the MMR first increased, then stabilized and then decreased. After introduction of checkpoint inhibitors in 2011 and TKIs in 2013, significant reduction in melanoma mortality rate (MMR) was seen during 2013-2017 in the United States, even in the setting of increasing melanoma incidence. This likely reflects a benefit from the availability of effective therapies in the last decade. These treatment options are now also approved for use in the adjuvant setting, primarily after 2017. It will be interesting to see if a further significant reduction in MMR will be seen. It may also be worthwhile to study real-world population trends in other cancers where similar treatments have been found to be effective in recent years.[Table: see text]
Diagnostic endoscopic submucosal dissection for colorectal lesions with suspected deep invasion
Authors: Adrien Patenotte, Clara Yzet, Timothée Wallenhorst, Fabien Subtil, Sarah Leblanc, Marion Schaefer, Thomas Walter, Thomas Lambin, Tanguy Fenouil, Pierre Lafeuille, Jean-Baptiste Chevaux, Romain Legros, Florian Rostain, Jérôme Rivory, Jérémie Jacques, Vincent Lépilliez, Mathieu Pioche
Journal: Endoscopy (2022)

Abstract Background Endoscopic submucosal dissection (ESD) is potentially a curative treatment for T1 colorectal cancer under certain conditions. The aim of this study was to evaluate the feasibility and effectiveness of ESD for lesions with a suspicion of focal deep invasion. Methods In this retrospective multicenter study, consecutive patients with colorectal neoplasia displaying a focal (&lt; 15 mm) deep invasive pattern (FDIP) that were treated by ESD were included. We excluded ulcerated lesions (Paris III), lesions with distant metastasis, and clearly advanced tumors (tumoral strictures). Results 124 patients benefited from 126 diagnostic dissection attempts for FDIP lesions. Dissection was feasible in 120/126 attempts (95.2 %) and, where possible, the en bloc and R0 resection rates were 95.8 % (115/120) and 76.7 % (92/120), respectively. Thirty-three resections (26.2 %) were for very low risk tumors, so considered curative, and 38 (30.2 %) were for low risk lesions. Noncurative R0 resections were for lesions with lymphatic or vascular invasion (LVI; n = 8), or significant budding (n = 9), and LVI + budding combination (n = 4). Conclusion ESD is feasible and safe for colorectal lesions with an FDIP ≤ 15 mm. It was curative in 26.6 % of patients and could be a valid option for a further 30.6 % of patients with low risk T1 cancers, especially for frail patients with co-morbidities.
Heart Failure: An Underappreciated Complication of Diabetes. A Consensus Report of the American Diabetes Association
Authors: Rodica Pop-Busui, James L. Januzzi, Dennis Bruemmer, Sonia Butalia, Jennifer B. Green, William B. Horton, Colette Knight, Moshe Levi, Neda Rasouli, Caroline R. Richardson
Journal: Diabetes Care (2022)

Heart failure (HF) has been recognized as a common complication of diabetes, with a prevalence of up to 22% in individuals with diabetes and increasing incidence rates. Data also suggest that HF may develop in individuals with diabetes even in the absence of hypertension, coronary heart disease, or valvular heart disease and, as such, represents a major cardiovascular complication in this vulnerable population; HF may also be the first presentation of cardiovascular disease in many individuals with diabetes. Given that during the past decade, the prevalence of diabetes (particularly type 2 diabetes) has risen by 30% globally (with prevalence expected to increase further), the burden of HF on the health care system will continue to rise. The scope of this American Diabetes Association consensus report with designated representation from the American College of Cardiology is to provide clear guidance to practitioners on the best approaches for screening and diagnosing HF in individuals with diabetes or prediabetes, with the goal to ensure access to optimal, evidence-based management for all and to mitigate the risks of serious complications, leveraging prior policy statements by the American College of Cardiology and American Heart Association.
Pathogenic <i>TP53</i> variant allele frequency across different somatic tissues in two patients with mosaic Li-Fraumeni.
Authors: Tin-Yun Tang, Duncan Stearns, Alexander Miron, Anna Mitchell
Journal: Journal of Clinical Oncology (2022)

10582 Background: The integration of germline genetic testing, frequently from blood, into routine oncological care has increased the frequency at which pathogenic TP53 mutations are found in a variant allele frequency (VAF) range suggestive of either mosaic Li-Fraumeni Syndrome or clonal hematopoiesis of indeterminate potential (CHIP). Mosaic LFS is a rare and poorly described phenomenon wherein a pathogenic TP53 mutation is dispersed in low levels through multiple somatic tissues after stochastically developing during early embryogenesis. In comparison, CHIP is restricted to the bone marrow niche. Germline mosaicism in Li-Fraumeni Syndrome (LFS) is inferred when genomic DNA from a second source recapitulates the exact same TP53 mutation. Given the challenges with sample acquisition, mosaicism has not been previously described in depth in the medical literature. Methods: Two pediatric patients with LFS-associated cancers (glioblastoma, osteosarcoma &amp; ALL respectively) underwent clinical genetics evaluation and were found to have pathogenic TP53 mutations. Initial genetic testing was performed in a CLIA/CAP environment through a send out test or internally. A broad array of somatic tissues was collected at autopsy with subsequent DNA isolation and amplicon sequencing in triplicate to determine the mean VAF of the pathogenic TP53 allele. Results: For both patients, the initial germline test suggesting mosaic LFS had a VAF between 20-30%. Confirmatory intent fibroblast culture in Patient 1 was reported as negative by an external clinical lab and Patient 2’s VAF was much lower. The VAFs for the rest of the somatic tissues as well as in their corresponding cancers are reported below (Table) as means and standard error of the triplicate. Despite the negative fibroblast culture, Patient 1 did demonstrate mutant TP53 in other tissues, confirming mosaicism. Conclusions: The proportion of pathogenic alleles is highly heterogeneous amongst different somatic tissues in mosaic LFS patients. Although CHIP exclusion through germline testing of cultured skin fibroblasts is common, our patients’ skin samples were amongst the tissues with the lowest VAFs. Mosaicism should be highly suspected when tumor sequencing demonstrates an identical mutation to the putative germline mosaic one even with equivocal fibroblast culture results. [Table: see text]
Targeting of GSDMD sensitizes HCC to anti-PD-1 by activating cGAS pathway and downregulating PD-L1 expression
Authors: Tingting Lv, Xiaofeng Xiong, Wei Yan, Mei Liu, Hongwei Xu, Qin He
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Gasdermin D (GSDMD) is well known as a downstream of inflammasomes. However, the roles of GSDMD itself in hepatocellular carcinoma (HCC) remain unclear. Methods Two independent cohorts of patients with HCC were analyzed to evaluate the pathological relevance of GSDMD/pTBK1/PD-L1. GSDMD knockout (GSDMD-/-) mice, Alb-Cre mice administered with an adeno-associated virus (AAV) vector that expressed the gasdermin-N domain (AAV9-FLEX-GSDMD-N) and their wild-type littermates were used to induce hepatocarcinogenesis or metastatic HCC. Combination of anti-programmed cell death protein-1 (PD-1) and GSDMD inhibitor dimethyl fumarate (DMF) was used to test for improved therapeutic efficacy. RNA sequencing was used to explore the mechanisms how GSDMD promoted HCC progression. Results The expression of GSDMD and GSDMD-N was upregulated in HCC tissues or metastatic HCC tissues and positive GSDMD expression indicated grim prognosis. Diethylnitrosamine/carbon tetrachloride or thioacetamide-treated GSDMD-/- mice exhibited decreased liver tumors. In contrast, AAV9-FLEX-GSDMD-N promoted hepatocarcinogenesis. RNA sequencing manifested that knockout of GSDMD impacted the cyclic GMP-AMP synthase (cGAS) pathway and immune-associated pathway. GSDMD damped cGAS activation by promoting autophagy via outputting potassium (K+) and promoted programmed death ligand-1 (PD-L1) expression by histone deacetylases/signal transducer and activator of transcription 1 (STAT1)-induced transactivation of PD-L1 via importing calcium (Ca2+). High Mobility Group Box 1/toll-like receptor 4 (TLR4)/caspase-1 pathway contributed to the overexpression and cleavage of GSDMD. Anti-PD-1 combining with DMF largely impaired HCC progression and metastasis. Conclusions Targeting GSDMD could promote expression of interferons through inactivation of cGAS pathway and downregulated the PD-L1 expression. Therefore, combined anti-PD-1 and GSDMD inhibitor might serve as an effective treatment option for patients with HCC with GSDMD upregulation.
CCTG BL13 a randomized phase II trial assessing trimodality therapy with or without adjuvant durvalumab to treat patients with muscle-invasive bladder cancer (NCT03768570).
Authors: Wassim Kassouf, Simon J. Crabb, Ignacio Duran, Michael Donald Brundage, M. Neil Reaume, Alice Dragomir, Alexander William Wyatt, Francisco Emilio Vera Badillo, Himu Lukka, Tamim Niazi, Luis Souhami, Srikala S. Sridhar, Gareth Owen Griffiths, Doris Howell, Harriet Richardson, Marina Djurfeldt, Keyue Ding, Wendy R. Parulekar
Journal: Journal of Clinical Oncology (2022)

TPS4619 Background: Immunotherapy improves outcomes in the advanced (Bellmunt 2019; Powles 2020) as well as in the adjuvant setting post cystectomy (Bajorin 2021) for muscle invasive bladder cancer (MIBC) patients. Trimodality treatment (TMT) consisting of transurethral resection of bladder tumor (TURBT) followed by chemoradiotherapy (CRT) may be considered an alternative to radical cystectomy in MIBC. The role of radiotherapy and chemotherapy as immune system stimulants provides a rationale to evaluate the anticancer activity of checkpoint inhibitors in this patient population. Durvalumab, an anti PDL1 inhibitor, administered after CRT leads to improvement in PFS and OS in patients with locally advanced NSCLC, which further supports the rationale for this study (Antonia 2017, 2018). We hypothesized that durvalumab will improve outcomes in patients with MIBC when administered in the adjuvant setting after completion of trimodality therapy. Methods: CCTG BL13 is a Canadian Cancer Trials Group, randomized phase II trial in patients with stage T2-T4a N0M0, urothelial carcinoma treated with TURBT followed by radiotherapy with concurrent chemotherapy. Treatment arms consist of durvalumab 1500 mg IV q 4 weeks for 12 months versus surveillance. The primary objective: to compare disease free survival (DFS) between arms (RECIST 1.1, investigator assessed). Secondary endpoints include a non muscle-invasive bladder cancer recurrence rate (&lt; T2); locoregional control rate; overall survival; bladder intact DFS, patterns of disease recurrence; metastasis free survival; safety; quality of life ; economics evaluation. A pilot sub study (BL13F) has been activated and will evaluate the feasibility of electronic real-time patient self-reporting of immunotherapy related symptomatic adverse events using the SYMPTOM-IQ Tool on the uMotif Mobile Health Application (APP). Statistical Design: Randomization 1:1 balanced for stratification factors: ECOG PS; neoadjuvant chemotherapy; radiation field extent; T2 vs T3/T4; centre. Assuming a 2-year DFS rate 65% for patients on the control arm and estimated 12% improvement in the 2-year DFS rate (65% to 77% (HR 0.61)) with 80% power using a 1-sided 10% level test requires a sample size of 190 including 5% drop out rate. Conduct to Date: Study activation Dec 2018. Enrollment as of January 31 2022: 49. The DSMC reviewed and recommended trial continuation in November 2021. Clinical trial information: NCT03768570.
In This Issue
Authors: Eva Schaefer, Helen Wang, Hannah Karp, Clifford Meyer, Paloma Cejas, Micah Gearhart, Emmalee Adelman, Iman Fares, Annie Apffel, Klothilda Lim, Yingtian Xie, Christopher Gibson, Monica Schenone, H Murdock, Eunice Wang, Lukasz Gondek, Martin Carroll, Rahul Vedula, Eric Winer, Jacqueline Garcia, Richard Stone, Marlise Luskin, Steven Carr, Henry Long, Vivian Bardwell, Maria Figueroa, R Lindsley
Journal: Blood Cancer Discovery (2022)

Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer.Unlike polycomb repressive complex 2 (PRC2), the role of PRC1 in oncogenesis and therapy resistance is not well-defined.Here, we demonstrate that highly recurrent mutations of the PRC1 subunits BCOR and BCORL1 in leukemia disrupt assembly of a noncanonical PRC1.1 complex, thereby selectively unlinking the RING-PCGF enzymatic core from the chromatin-targeting auxiliary subcomplex.As a result, BCOR-mutated PRC1.1 is localized to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci.We define a set of functional targets that drive aberrant oncogenic signaling programs in PRC1.1-mutated cells and primary patient samples.Activation of these PRC1.1 targets in BCOR-mutated cells confers acquired resistance to treatment while sensitizing to targeted kinase inhibition.Our study thus reveals a novel epigenetic mechanism that explains PRC1.1 tumor-suppressive activity and identifies a therapeutic strategy in PRC1.1-mutated cancer. SIGNIFICANCE:We demonstrate that BCOR and BCORL1 mutations in leukemia unlink PRC1.1 repressive function from target genes, resulting in epigenetic reprogramming and activation of aberrant cell signaling programs that mediate treatment resistance.Our study provides mechanistic insights into the pathogenesis of PRC1.1-mutated leukemia that inform novel therapeutic approaches.